Abstract:A genome-wide microscopy screen identifies proteins localized to Cajal bodies,
paraspeckles, and other known and previously uncharacterized nuclear
subcompartments.
“…An additional report from another group studying Cajal body structure and function identified a role for TOE1 in Cajal body formation, as well as in RNA splicing, although its precise role in RNA splicing is yet to be determined (4). Together, the combination of the published work points to the involvement of TOE1 in the regulation of multiple cellular functions including those involving growth regulation and RNA metabolism.…”
Target of Egr1 (TOE1) is a nuclear protein localized primarily in nucleoli and Cajal bodies that was identified as a downstream target of the immediate early gene Egr1. TOE1 displays a functional deadenylation domain and has been shown to participate in spliceosome assembly. We report here that TOE1 can function as an inhibitor of HIV-1 replication and show evidence that supports a direct interaction of TOE1 with the viral specific transactivator response element as part of the inhibitory mechanism. In addition, we show that TOE1 can be secreted by activated CD8 + T lymphocytes and can be cleaved by the serine protease granzyme B, one of the main components of cytotoxic granules. Both full-length and cleaved TOE1 can spontaneously cross the plasma membrane and penetrate cells in culture, retaining HIV-1 inhibitory activity. Antiviral potency of TOE1 and its cell-penetrating capability have been identified to lie within a 35-amino-acid region containing the nuclear localization sequence.W e previously reported the cloning of a gene encoding the Target Of Egr1 (TOE1) protein as a target for the immediate early transcription factor Egr1 using ChIP-based methodology and its partial characterization as an inhibitor of cell growth (1). Mechanistically, TOE1 overexpression correlates with up-regulation of the cyclin-dependent kinase inhibitor p21 and produces an accumulation of cells in the G2/M phase of the cell cycle. Subsequently, we found that TOE1 is able to bind to the C-terminal tetramerization domain of the p53 tumor suppressor protein and enhances its transcriptional activity, further underscoring the potential importance of a role for TOE1 in the cellular growth inhibition through cell cycle modulation (2).A previous report from another group studying RNA turnover and investigating human homologs for the yeast Ccr4p and Caf1p/ Pop2p found that TOE1 possesses RNA deadenylase catalytic activity in vitro (3). Interestingly, only transfection of TOE1 with a deletion in its nuclear localization signal, restricting cytoplasmic localization of TOE1, displayed deadenylase activity in cultured cells.Although heterokaryon experiments using HeLa and NIH 3T3 cells detected nucleocytoplasmic shuttling, it remains uncertain whether retention of TOE1 in the cytoplasm occurs to permit effective deadenylation of RNA substrates. An additional report from another group studying Cajal body structure and function identified a role for TOE1 in Cajal body formation, as well as in RNA splicing, although its precise role in RNA splicing is yet to be determined (4). Together, the combination of the published work points to the involvement of TOE1 in the regulation of multiple cellular functions including those involving growth regulation and RNA metabolism.With regard to human disease pathology, clues for a biological role for TOE1 were revealed in a study by investigators in search for the identity of an endogenous noncytotoxic proteinaceous factor secreted from CD8 + T lymphocytes able to control the replication of HIV-1 in infected...
“…An additional report from another group studying Cajal body structure and function identified a role for TOE1 in Cajal body formation, as well as in RNA splicing, although its precise role in RNA splicing is yet to be determined (4). Together, the combination of the published work points to the involvement of TOE1 in the regulation of multiple cellular functions including those involving growth regulation and RNA metabolism.…”
Target of Egr1 (TOE1) is a nuclear protein localized primarily in nucleoli and Cajal bodies that was identified as a downstream target of the immediate early gene Egr1. TOE1 displays a functional deadenylation domain and has been shown to participate in spliceosome assembly. We report here that TOE1 can function as an inhibitor of HIV-1 replication and show evidence that supports a direct interaction of TOE1 with the viral specific transactivator response element as part of the inhibitory mechanism. In addition, we show that TOE1 can be secreted by activated CD8 + T lymphocytes and can be cleaved by the serine protease granzyme B, one of the main components of cytotoxic granules. Both full-length and cleaved TOE1 can spontaneously cross the plasma membrane and penetrate cells in culture, retaining HIV-1 inhibitory activity. Antiviral potency of TOE1 and its cell-penetrating capability have been identified to lie within a 35-amino-acid region containing the nuclear localization sequence.W e previously reported the cloning of a gene encoding the Target Of Egr1 (TOE1) protein as a target for the immediate early transcription factor Egr1 using ChIP-based methodology and its partial characterization as an inhibitor of cell growth (1). Mechanistically, TOE1 overexpression correlates with up-regulation of the cyclin-dependent kinase inhibitor p21 and produces an accumulation of cells in the G2/M phase of the cell cycle. Subsequently, we found that TOE1 is able to bind to the C-terminal tetramerization domain of the p53 tumor suppressor protein and enhances its transcriptional activity, further underscoring the potential importance of a role for TOE1 in the cellular growth inhibition through cell cycle modulation (2).A previous report from another group studying RNA turnover and investigating human homologs for the yeast Ccr4p and Caf1p/ Pop2p found that TOE1 possesses RNA deadenylase catalytic activity in vitro (3). Interestingly, only transfection of TOE1 with a deletion in its nuclear localization signal, restricting cytoplasmic localization of TOE1, displayed deadenylase activity in cultured cells.Although heterokaryon experiments using HeLa and NIH 3T3 cells detected nucleocytoplasmic shuttling, it remains uncertain whether retention of TOE1 in the cytoplasm occurs to permit effective deadenylation of RNA substrates. An additional report from another group studying Cajal body structure and function identified a role for TOE1 in Cajal body formation, as well as in RNA splicing, although its precise role in RNA splicing is yet to be determined (4). Together, the combination of the published work points to the involvement of TOE1 in the regulation of multiple cellular functions including those involving growth regulation and RNA metabolism.With regard to human disease pathology, clues for a biological role for TOE1 were revealed in a study by investigators in search for the identity of an endogenous noncytotoxic proteinaceous factor secreted from CD8 + T lymphocytes able to control the replication of HIV-1 in infected...
“…2). The unique domains of each protein likely mediate subcellular localization, substrate, and regulatory partner specificity, as has been observed for CAF1z [30,35,36], PDE12 [37–39], PARN [36,40–42], and PNLDC1 [43–46]. NOCT biological function is likely further defined by its expression pattern and subcellular localization.10.1080/15476286.2018.1526541-F0002Figure 2.NOCT is related to CCR4-type deadenylases and contains a conserved EEP catalytic domain.…”
Section: Post-transcriptional Control Of Mrna Abundance and Stabilitymentioning
Post-transcriptional control of messenger RNA (mRNA) is an important layer of gene regulation that modulates mRNA decay, translation, and localization. Eukaryotic mRNA decay begins with the catalytic removal of the 3′ poly-adenosine tail by deadenylase enzymes. Multiple deadenylases have been identified in vertebrates and are known to have distinct biological roles; among these proteins is Nocturnin, which has been linked to circadian biology, adipogenesis, osteogenesis, and obesity. Multiple studies have investigated Nocturnin’s involvement in these processes; however, a full understanding of its molecular function remains elusive. Recent studies have provided new insights by identifying putative Nocturnin-regulated mRNAs in mice and by determining the structure and regulatory activities of human Nocturnin. This review seeks to integrate these new discoveries into our understanding of Nocturnin’s regulatory functions and highlight the important remaining unanswered questions surrounding its regulation, biochemical activities, protein partners, and target mRNAs.
“…Fam118B is an uncharacterized protein and was first identified as a potential component of Cajal bodies in a proteomic screen that we performed recently (Fong et al, 2013). To confirm the expression and localization of Fam118B in cells, we generated rabbit polyclonal antibodies against Fam118B.…”
Section: Fam118b Is a Newly Identified Component Of Cajal Bodies And mentioning
confidence: 99%
“…5C,D), ruling out a role for potential offtarget effects of Fam118B siRNA. To further validate the roles of Fam118B in pre-mRNA splicing under physiological conditions, we selected eight endogenous genes (DPP8, DDX20, NOSIP, ACP1, CSDA, CD44, STK6 and ZNF207) and used quantitative real-time PCR (qRT-PCR) to evaluate the abundance of the spliced mRNA as described previously (Fong et al, 2013). We found that the depletion of Fam118B reduced the levels of spliced mRNA by 10-63% whereas the depletion of coilin resulted in a similar reduction of 26-67% (Fig.…”
Section: Depletion Of Fam118b Causes Diminished Splicing Capacity Andmentioning
Cajal bodies (CBs) are specialized and dynamic compartments in nucleus that are involved in small nuclear ribonucleoprotein (snRNP) biogenesis. Because of the dynamic and multifunctional roles of CBs, it is of great interest to identify components in CBs to better understand their functions. We performed a genome-wide screen to identify proteins that co-localize with Coilin, the CB marker protein. In this study, we identified and characterized Fam118B as a novel component of CBs. Fam118B is widely expressed in a variety of cell lines derived from various origins. Overexpression of Fam118B changes the canonical morphology of CBs, whereas depletion of Fam118B disrupts the localization of CB components, including Coilin, the survival of motor neuron protein (SMN) and the Sm protein D1 (SmD1). Moreover, depletion ofFam118B reduces splicing capacity and inhibits cell proliferation. In addition, Fam118B associates with Coilin and SMN proteins. Fam118B depletion reduces symmetric dimethylarginine modification of SmD1, which in turn diminishes SMN binding to this Sm protein. Taken together, these data indicate that Fam118B, by regulating SmD1 symmetric dimethylarginine modification, plays an important role in CB formation, snRNP biogenesis and cell viability.
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